Ribociclib

Absorption

Ribociclib is orally bioavailable, highly selective inhibitor of CDK4/6 kinases with inhibitory IC50 concentrations in the low nanomolar range. Following oral dosing, ribociclib was rapidly absorbed with median Tmax ranging from 1 to 5 hours. Plasma concentrations increased approximately 2- to 3-fold from Cycle 1 Day 1 to Cycle 1 Day 18/21 due to accumulation, with steady state reached by approximately Day 8 on the basis of trough concentrations after repeated daily dosing. Dose-proportionality analyses demonstrated that exposure to ribociclib increased with dose, with both Cmax and area under the curve (AUC) increasing slightly more than proportional to dose, over the dose range 50–1,200 mg/day

Description

LEE011 is a cyclin-dependent kinase (CDK) inhibitor that targets cyclin D1/CDK4 and cyclin D3/CDK6 at nanomolar concentrations. It inhibits retinoblastoma protein phosphorylation, which prevents CDK-mediated G₁-S phase transition, arresting the cell cycle in the G₁ phase, suppressing DNA synthesis, and inhibiting cancer cell growth. LEE011 has been shown to reduce proliferation in 12 of 17 human neuroblastoma-derived cell lines by inducing cytostasis (mean IC₅₀ = 306 nM in sensitive lines).

Characteristics

Class: serine/threonine protein kinase
Treatment: Breast cancer
Oral bioavailability = 66%
Elimination half-life = 32 h
Protein binding = 70%

The Uses of Ribociclib

LEE 011 can be used in biological study of kinome-wide RNA interference screen reveals a role for PDK1 in acquired resistance to CDK4/6 inhibition in ER-positive breast cancer.

Background

Ribociclib is a selective cyclin-dependent kinase inhibitor, a class of drugs that help slow the progression of cancer by inhibiting two proteins called cyclin-dependent kinase 4 and 6 (CDK4/6). These proteins, when over-activated, can enable cancer cells to grow and divide too quickly. Targeting CDK4/6 with enhanced precision may play a role in ensuring that cancer cells do not continue to replicate uncontrollably. Ribociclib was approved by the U.S. FDA in March, 2017 as Kisqali.

Indications

Kisqali (ribociclib) is a selective cyclin-dependent kinase inhibitor, a class of drugs that help slow the progression of cancer by inhibiting two proteins called cyclin-dependent kinase 4 and 6 (CDK4/6). These proteins, when over-activated, can enable cancer cells to grow and divide too quickly. Targeting CDK4/6 with enhanced precision may play a role in ensuring that cancer cells do not continue to replicate uncontrollably.

Mechanism of action

Ribociclib is a dual cdk4/cdk6 inhibitor. Induces G1 phase cell cycle arrest and senescence in neuroblastoma cell lines (IC50 = 306 nM). Delays tumor growth in vivo.

Clinical Use

Protein kinase inhibitor:
Treatment of breast cancer

Clinical Use

Ribociclib was first approved in 2017 as the second CDK4/6 (cyclin-dependent kinase) inhibitor in combination with aromatase inhibitor as initial endocrine-based therapy for the treatment of postmenopausal women with hormone receptor positive (HR+), human epidermal growth factor receptor-2 negative (HER2?) advanced or metastatic breast cancer. In 2018, its label was expanded to pre/perimenopausal women with HR+/HER2? advanced or metastatic breast cancer.

Drug interactions

Potentially hazardous interactions with other drugs
The concomitant use of strong CYP3A4 inhibitors including, but not limited to, the following must be avoided: clarithromycin, indinavir, itraconazole, ketoconazole, lopinavir, ritonavir, nefazodone, nelfinavir, posaconazole, saquinavir, telaprevir, telithromycin, verapamil and voriconazole.
The concomitant use of strong CYP3A4 inducers may therefore lead to decreased exposure and consequently a risk for lack of efficacy. The concomitant use of strong CYP3A4 inducers should be avoided, including, but not limited to, phenytoin, rifampicin, carbamazepine and St John's wort.
Caution and monitoring for toxicity are advised during concomitant treatment with sensitive substrates of drug transporters P-gp, BCRP, OATP1B1/1B3, OCT1, OCT2, MATE1 and BSEP which exhibit a narrow therapeutic index, including but not limited to digoxin, pravastatin, rosuvastatin and metformin.
Co-administration of Kisqali with medicinal products with a known potential to prolong the QT interval such as anti-arrhythmic medicinal products (including, but not limited to, amiodarone, disopyramide, procainamide, quinidine and sotalol), and other medicinal products that are known to prolong the QT interval (including, but not limited to, chloroquine, halofantrine, clarithromycin, haloperidol, methadone, moxifloxacin, pimozide and intravenous ondansetron) should be avoided.

Side Effects

The most common side effects of ribociclib include infections, low levels of white blood cells, headache, cough, nausea (feeling sick), vomiting, diarrhoea, constipation, tiredness, hair loss and rash.The most common severe side effects include infections, low levels of red and white blood cells, vomiting, abnormal blood tests for liver function and low levels of phosphate in the blood (hypophosphataemia).

Metabolism

Ribociclib is hepatically metabolised via CYP3A4 by oxidation. Ribociclib was the main circulating drug in plasma (44%). The major circulating metabolites included metabolite M13 (CCI284, N-hydroxylation), M4 (LEQ803, N-demethylation), and M1 (secondary glucuronide). Clinical activity of ribociclib was due mainly to parent drug, with negligible contribution from circulating metabolites. Unchanged drug accounted for 17.3% and 12.1% of the dose in faeces and urine, respectively. Metabolite LEQ803 represented approximately 13.9% and 3.74% of the administered dose in faeces and urine, respectively. Numerous other metabolites were detected in both faeces and urine in minor amounts (≤2.78%).
Ribociclib and its metabolites are eliminated mainly via faeces (69.1%), with a small contribution from the renal route (22.6%).

storage

Store at -20°C

References

1) Rader?et al.?(2013),?Dual CDK4/6 inhibition induces cell-cycle arrest and senescence in neuroblastoma; Clin. Cancer Res.?19?6173 2) Kim?et al. (2013),?LEE011: an orally bioavailable, selective small-molecule inhibitor of CDK4/6 – reactivating Rb in cancer; Mol. Cancer Ther.?12?PR02 3) Tripathy?et al.?(2017),?Ribociclib(LEE011): mechanism of action and clinical impact of this selective cyclin-dependent kinase 4/6 inhibitor in various solid tumors; Clin. Cancer Res. March 28, 201